The Wnt signaling pathway are involved in the control of embryonic development and neoplastic processes. Extracellular Wnt proteins are responsible for the growth and differentiation of many cell types, including in particular the growth, differentiation and regulation of osteoblasts, osteoclasts and adipocytes.
Many cancers are associated with bone tissues and can result in osteoblastic lesions such as those found in prostate cancer, or in osteolytic lesions such as those found in lung cancer, breast cancer, and multiple myeloma (e.g., Tian et al., 2003 New England J. Med. 349:2483-2494).
Members of the Wnt gene family encode secreted glycoproteins that are required for a variety of developmental processes (Fedi et al., 1999 J. Bio. Chem. 274:19465-19472). A Wnt family member protein initiates a signaling pathway that is important for the growth and differentiation of osteoblasts, which cause bone deposition. In addition to bone formation, bone resorption is an ongoing normal process conducted by cells known as osteoclasts. In contrast, receptor activator of nuclear factor-kappa B ligand (RANKL) is the final mediator of osteoclastic bone resorption, where it plays a major role in the pathogenesis of postmenopausal osteoporosis, as well as in bone loss associated with rheumatoid arthritis, metastatic cancer, multiple myeloma, aromatase inhibitor therapy and androgen deprivation therapy (see, e.g., Lewiecki (2006) Expert Opin Biol Ther. 6: 1041-50). Osteoprotegrin (OPG), which is expressed by osteoblasts, inhibits RANKL, thereby decreasing osteoclast activity and formation. The balance between anabolic bone formation and analytic bone resorption regulates normal bone density, while an increase in one or the other leads to increased bone density or increased bone loss, respectively.
Wnt binds and acts through other cell surface proteins and Wnt signaling can contribute to the neoplastic process. Furthermore, genetic alterations can affect a cellular protein complex known as adenomatous polyposis coli involving a protein β-catenin, and these complexes have been observed in cells of patients with diseases such as human colon cancer, melanomas, and hepatocellular carcinomas, indicating that aberrations of Wnt signaling pathways are relevant to the development of these and possibly other human cancers (Fedi et al., 1999 J. Bio. Chem. 274:19465-19472).
There are at least two families of proteins that inhibit Wnt signaling, namely the secreted frizzled-related family and the Dickkopf (DKK) family. The DKK family currently contains four family members, namely DKK1 (human DNA accno. NM—012242; PRT accno. O94907), DKK2 (human accno. NM—014421; PRT accno. NP—055236), DKK3 (human accno. NM—015881; PRT accno. AAQ88744), and DKK4 (human accno. NM—014420; PRT accno. NP—055235).
Dickkopf-1 (DKK1) is a secreted inhibitor of the Wnt/β-catenin signaling pathway. See, e.g., U.S. patent application 2005-0079173 to Niehrs; U.S. patent application 2004-0234515 to McCarthy. DKK1 possesses the ability to inhibit Wnt-induced axis duplication, and genetic analysis indicates that DKK1 acts upstream to inhibit Wnt signaling. DKK1 is also important in skeletal development as demonstrated by effects on the loss of bone structures in chicken and mouse embryos after exposure to elevated levels of DKK1 (Tian et al.; 2003 New England J. Med. 349:2483-2494). Elevated DKK1 serum levels has been associated with prostate cancer, and elevated DKK1 and RANKL levels in bone marrow plasma and peripheral blood in patients with multiple myeloma are associated with the presence of focal bone lesions See, e.g., Tian 2003, OMIM accno. 605189. DKK1 also plays a role in adipogenesis, chondrogenesis, proliferation of the gastrointestinal epithelial proliferation, bone loss associated with rheumatisms; and initiation of hair follicle placode formation. OMIM accno. 605189.
Dickkopf-4 (DKK4) is less well characterized but is likewise a secreted inhibitor of the Wnt pathway. DKK4 has been shown to be deposited in plaques in patients with Alzheimers disease and is expressed in muscle. Wnt has no known role in muscle development, therefore it is postulated herein that DKK4 has an inhibitory role on muscle development.
There is a need for compositions and methods to treat cancers and bone density abnormalities, including such agents that interfere or neutralize DKK1 and/or DKK4 mediated antagonism of Wnt signaling.